This invention relates to polymeric compounds useful as antitumor agents.
Various naturally-occurring and synthetic polyanionic materials have been investigated heretofore for their antitumor and related pharmaceutically active properties. One class of the synthetic polymers which has received considerable attention and study over the years is the class of polycarboxylates derived from ethylene/maleic anhydride (EMA) copolymers. The antitumor properties of these polymeric compounds were described at an early date by Regelson et al., Nature (London) 186, 778-80 (1960) and in Canadian Pat. No. 664,326, corresponding to U.S. Application Ser. No. 758,023, filed Oct. 28, 1958, now abandoned. According to the latter patent, the useful molecular weight of these polymers is said to range between 500 and 1.5 million. One of these polymers, the half-amide, half-ammonium salt of EMA having an average molecular weight of 20,000-30,000 was later reported to be chronically toxic in rodents and dogs. Mihich et al., Fed. Proc. Vol. 19, No. 1, Pt. 1, p. 142a, March 1960. Chronic toxicity also was later reported with the 2000-3000 molecular weight polymer in dogs by Mihich et al., Fed. Proc. Vol. 20, No. 1, Pt. 1, p. 407a, March 1961. These findings of toxicity militated against clinical testing of the polymers.
More recently, certain new derivatives of the EMA type copolymers having a relatively low average molecular weight of from about 300 to about 1500 were found to have far less toxicity than the higher molecular weight copolymers and to have more useful antitumor properties. These copolymers were derivatized to contain both a half-amide, half-carboxylate salt function and an imide function in which the latter function comprised from about 5% to about 40% by weight of the two functions. Further description of these derivatized copolymers can be had by reference to copending application Ser. No. 5638, filed Jan. 22, 1979, and assigned to a common assignee.
As described in said copending application Ser. No. 5638, the latter copolymers are preferably derivatized by ammoniation in organic solvents in a two-stage process. In the first stage, the EMA type copolymer is reacted with liquid ammonia in acetone to prepare the intermediate half-amide, half-ammmonium salt (AEMA). The AEMA precipitates out of solution and is recovered by filtration, centrifugation and the like separation procedures. The imide-containing derivative is then prepared in a second stage by reacting the intermediate AEMA with ammonia in a suitable solvent such as xylene or toluene at refluxing temperatures while concurrently removing water until the desired percentage of imide is formed.
It has been found subsequently that the aforesaid derivatization in organic solvents gives rise to undesirable by-product contaminants in the final product which are now desired to be avoided for pharmaceutical use of the product. These contaminants cause an undesirable darkening of the final product. Although the specific composition of the by-product contaminants has not been identified, it is known, for example, that aldol condensation can occur with acetone in basic media (as can be provided by ammonia) to yield compounds such as diacetone alcohol, mesityl oxide, phorone, isophorone and diacetone amine. See, for example, Fieser and Fieser, "Advanced Organic Chemistry", pp. 457-8, Reinhold Publishing Corporation, New York, 1961, and Royals, "Advanced Organic Chemistry", pp. 759-61, Prentice-Hall, Inc., New York, 1961. The present invention is directed to overcoming the problem of these and other such contaminants.
Elimination of organic solvents in the method of producing the copolymer derivatives is further desired to improve filterability during processing and to avoid the possibility of fire hazards with flammable materials.